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Adenosine-to-inosine RNA editing in the immune system: friend or foe?

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Abstract

Our body expresses sensors to detect pathogens through the recognition of expressed molecules, including nucleic acids, lipids, and proteins, while immune tolerance prevents an overreaction with self and the development of autoimmune disease. Adenosine (A)-to-inosine (I) RNA editing, catalyzed by adenosine deaminases acting on RNA (ADARs), is a post-transcriptional modification that can potentially occur at over 100 million sites in the human genome, mainly in Alu repetitive elements that preferentially form a double-stranded RNA (dsRNA) structure. A-to-I conversion within dsRNA, which may induce a structural change, is required to escape from the host immune system, given that endogenous dsRNAs transcribed from Alu repetitive elements are potentially recognized by melanoma differentiation-associated protein 5 (MDA5) as non-self. Of note, loss-of-function mutations in the ADAR1 gene cause Aicardi–Goutières syndrome, a congenital autoimmune disease characterized by encephalopathy and a type I interferon (IFN) signature. However, the loss of ADAR1 in cancer cells with an IFN signature induces lethality via the activation of protein kinase R in addition to MDA5. This makes cells more sensitive to immunotherapy, highlighting the opposing immune status of autoimmune diseases (overreaction) and cancer (tolerance). In this review, we provide an overview of insights into two opposing aspects of RNA editing that functions as a modulator of the immune system in autoimmune diseases and cancer.

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Abbreviations

A:

Adenosine

ADAR:

Adenosine deaminase acting on RNA

AGS:

Aicardi-Goutières syndrome

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid

APC:

Antigen-presenting cell

AZIN1:

Antizyme inhibitor 1

COPA:

Coatomer protein complex, subunit alpha

dsRNA:

Double-stranded RNA

DC:

Dendritic cell

DNMT:

DNA methyltransferase

DSH:

Dyschromatosis symmetrica hereditaria

eIF2α:

Eukaryotic initiation factor 2 alpha

EIF2AK2:

Eukaryotic translation initiation factor 2 alpha kinase 2

ERV:

Endogenous retroviruse

G:

Glycine

GABAA :

Type A gamma-aminobutyric acid

GABRA3:

GABAA receptor subunit α-3

I:

Inosine

IFN:

Interferon

ISG:

IFN-stimulated gene

KI:

Knock-in

KO:

Knockout

LINE:

Long interspersed element

LTR:

Long terminal repeat

MAVS:

Mitochondrial anti-viral-signaling protein

MDA5:

Melanoma differentiation-associated protein 5

MHC:

Major histocompatibility complex

miRNA:

MicroRNA

mTEC:

Medullary thymic epithelial cell

m7G:

5′Triphosphate-linked methylguanosine

N:

Asparagine

N1:

5′-Terminal nucleotide

OAS:

Oligoadenylate synthetase

ORF:

Open-reading frame

PAS:

Periodic acid-Schiff

PBMC:

Peripheral blood mononuclear cell

PD-L1:

Programmed cell-death ligand-1

PD-1:

Programmed cell death 1

PKR:

Protein kinase R

Pol:

Polymerase

Q:

Glutamine

R:

Arginine

RA:

Rheumatoid arthritis

RHOQ:

Ras Homolog Family Member Q

RIG-I:

Retinoic acid-inducible gene I

RLR:

RIG-I-like receptor

PRR:

Pattern recognition receptor

S:

Serine

SINE:

Short interspersed element

SLE:

Systemic lupus erythematosus

TCGA:

The Cancer Genome Atlas

TCR:

T-cell receptor

UTR:

Untranslated region

U:

Uridine

2′OMe:

2′-O-Methylation

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Acknowledgements

This work was supported by Grants-in-Aid (KAKENHI; 19K22580 and 19H04210 to Y. K., and 18K15186 and 15K19126 to T. N.) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, by grants from the Takeda Science Foundation (to Y. K. and T. N.), the Osaka Nanbyou Zaidan, The Naito Foundation, the Astellas Foundation for Research on Metabolic Disorders and The Mochida Memorial Foundation for Medical and Pharmaceutical Research (to T. N.), and by a Novartis Research Grant (to T. N.).

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  1. Department of RNA Biology and Neuroscience, Graduate School of Medicine, Osaka University, Suita, Osaka, 565-0871, Japan

    Taisuke Nakahama & Yukio Kawahara

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Nakahama, T., Kawahara, Y. Adenosine-to-inosine RNA editing in the immune system: friend or foe?. Cell. Mol. Life Sci. 77, 2931–2948 (2020). https://doi.org/10.1007/s00018-020-03466-2

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